@misc{10818/59972,
year = {2022},
url = {http://hdl.handle.net/10818/59972},
abstract = {IMPORTANCE Rare germline genetic variants in several genes are associated with increased breast cancer (BC) risk, but their precise contributions to different disease subtypes are unclear. This information is relevant to guidelines for gene panel testing and risk prediction. OBJECTIVE To characterize tumors associated with BC susceptibility genes in large-scale population- or hospital-based studies. DESIGN, SETTING, AND PARTICIPANTS The multicenter, international case-control analysis of the BRIDGES study included 42 680 patients and 46 387 control participants, comprising women aged 18 to 79 years who were sampled independently of family history from 38 studies. Studies were conducted between 1991 and 2016. Sequencing and analysis took place between 2016 and 2021. EXPOSURES Protein-truncating variants and likely pathogenic missense variants in ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, RAD51D, and TP53. MAIN OUTCOMES AND MEASURES The intrinsic-like BC subtypes as defined by estrogen receptor, progesterone receptor, and ERBB2 (formerly known as HER2) status, and tumor grade; morphology; size; stage; lymph node involvement; subtype-specific odds ratios (ORs) for carrying protein-truncating variants and pathogenic missense variants in the 9 BC susceptibility genes. RESULTS The mean (SD) ages at interview (control participants) and diagnosis (cases) were 55.1 (11.9) and 55.8 (10.6) years, respectively; all participants were of European or East Asian ethnicity. There was substantial heterogeneity in the distribution of intrinsic subtypes by gene. RAD51C, RAD51D, and BARD1 variants were associated mainly with triple-negative disease (OR, 6.19 [95% CI, 3.17-12.12]; OR, 6.19 [95% CI, 2.99-12.79]; and OR, 10.05 [95% CI, 5.27-19.19], respectively). CHEK2 variants were associated with all subtypes (with ORs ranging from 2.21-3.17) except for triple-negative disease. For ATM variants, the association was strongest for the hormone receptor (HR)+ERBB2− high-grade subtype (OR, 4.99; 95% CI, 3.68-6.76). BRCA1 was associated with increased risk of all subtypes, but the ORs varied widely, being highest for triple-negative disease (OR, 55.32; 95% CI, 40.51-75.55). BRCA2 and PALB2 variants were also associated with triple-negative disease. TP53 variants were most strongly associated with HR+ERBB2+ and HR-ERBB2+ subtypes. Tumors occurring in pathogenic variant carriers were of higher grade. For most genes and subtypes, a decline in ORs was observed with increasing age. Together, the 9 genes were associated with 27.3% of all triple-negative tumors in women 40 years or younger. CONCLUSIONS AND RELEVANCE The results of this case-control study suggest that variants in the 9 BC risk genes differ substantially in their associated pathology but are generally associated with triple-negative and/or high-grade disease. Knowing the age and tumor subtype distributions associated with individual BC genes can potentially aid guidelines for gene panel testing, risk prediction, and variant classification and guide targeted screening strategies. © 2022 American Medical Association},
publisher = {JAMA Oncology},
title = {Pathology of tumors associated with pathogenic germline variants in 9 breast cancer susceptibility genes},
doi = {10.1001/jamaoncol.2021.6744},
author = {Mavaddat N. and Dorling L. and Carvalho S. and Allen J. and González-Neira A. and Keeman R. and Bolla M.K. and Dennis J. and Wang Q. and Ahearn T.U. and Andrulis I.L. and Beckmann M.W. and Behrens S. and Benitez J. and Bermisheva M. and Blomqvist C. and Bogdanova N.V. and Bojesen S.E. and Briceno I. and Brüning T. and Camp N.J. and Campbell A. and Castelao J.E. and Chang-Claude J. and Chanock S.J. and Chenevix-Trench G. and Christiansen H. and Czene K. and Dörk T. and Eriksson M. and Evans D.G. and Fasching P.A. and Figueroa J.D. and Flyger H. and Gabrielson M. and Gago-Dominguez M. and Geisler J. and Giles G.G. and Guénel P. and Hadjisavvas A. and Hahnen E. and Hall P. and Hamann U. and Hartikainen J.M. and Hartman M. and Hoppe R. and Howell A. and Jakubowska A. and Jung A. and Khusnutdinova E.K. and Kristensen V.N. and Li J. and Lim S.H. and Lindblom A. and Loizidou M.A. and Lophatananon A. and Lubiński J. and Madsen M.J. and Mannermaa A. and Manoochehri M. and Margolin S. and Mavroudis D. and Milne R.L. and Taib N.A.M. and Morra A. and Muir K. and Obi N. and Osorio A. and Park-Simon T.-W. and Peterlongo P. and Radice P. and Saloustros E. and Sawyer E.J. and Schmutzler R.K. and Shah M. and Sim X. and Southey M.C. and Thorne H. and Tomlinson I. and Torres D. and Truong T. and Yip C.H. and Spurdle A.B. and Vreeswijk M.P.G. and Dunning A.M. and García-Closas M. and Pharoah P.D.P. and Kvist A. and Muranen T.A. and Nevanlinna H. and Teo S.H. and Devilee P. and Schmidt M.K. and Easton D.F.},
}